1. Field of the Invention
The present invention pertains to the field of biochemistry and more specifically to the field of prodrugs of metabolic agents and related methods.
2. Description of the Related Art
The use of isoflavones as metabolic agents is described in U.S. Pat. No. 4,163,746 to Feuer, assigned to Chinoin Gyogyszer es Vegyeszeti Termekek Gyara Rt. of Hungary (xe2x80x9cthe Feuer ""746 patentxe2x80x9d). The Feuer ""746 patent identifies a class of isoflavones characterized as possessing a methyl group at the 5-carbon position and a hydroxyl or ether group at the 7 carbon position. The Feuer ""746 patent lists 5-methyl-7-methoxy-isoflavone, 5-methyl-7-ethoxy-isoflavone, 5-methyl-7-(2-hydroxy-ethoxy)-isoflavone, and 5-methyl-7-isopropoxy-isoflavone as preferred isoflavones.
The Feuer ""746 patent purports that its class of isoflavones were shown to have utility in promoting anabolic activity and increasing calcium, phosphorous, potassium, and nitrogen retention to a significant degree. The list of preferred isoflavones mentioned above also is purported to produce a significant weight gain increase in domestic animals, with the weight surplus consisting of meat, rather than fat. According to the Feuer ""746 patent, perhaps the most significant advantage of its class of isoflavones over conventional anabolic agents was that its isoflavones did not produce androgenic or liver damaging side effects. Due to its anabolic properties, the isoflavones of the Feuer ""746 patent are described as having utility in the treatment of diseases, and particular utility in the treatment of osteoporosis of gerontological and immobilation origin.
Without necessarily wishing to be bound by any theory, it is believed that the isoflavones described in the Feurer ""746 patent, such as 5-methyl- 7-methoxy-isoflavone, are prodrugs, that is, a compound that itself has no anabolic activity but, when administered in the body, is metabolized or converted into a natural or desired form, 7-hydroxy-5-methyl-isoflavone, which promotes anabolic activity. Thus, such prodrugs, i.e., 5-methyl-7-methoxy-isoflavone, become substrates for in vivo bioconversion into the desired parent compounds. (Incidentally, if 7-hydrox-5-methyl-isoflavone were administered directly, i.e., not in a prodrug state, the liver would likely metabolize substantially all of the 7-hydroxy-5-methyl-isoflavone during the first pass.)
Based on findings of the Feurer ""746 patent and other reported research, the compound 5-methyl-7-methoxy-isoflavone is commercially sold as a nutritional supplement and advertised as an anabolic agent for promoting muscle mass gains and body fat composition losses, while not causing adverse side effects associated with the use of steroids.
However, the effectiveness of the prodrug 5-methyl-7-methoxy isoflavone has been limited due to difficulties that the human body encounters in converting the prodrug to its parent isoflavone in vivo. In some instances, its conversion into the desired parent compound, 7-hydroxy-5-methyl-isoflavone, is limited, for example, because it is removed from the system through the xe2x80x9cfirst pass effect,xe2x80x9d wherein the compound is metabolized by the liver prior to reaching general circulation. A large proportion of the prodrug also either does not undergo conversion or converts into undesirable products. It is estimated that approximately 50% of the prodrug 5-methyl-7-methoxy isoflavone administered to a human is converted in vivo to 7-hydroxy-5-methyl-isoflavone. Even where the desired bioconversion occurs, the rate of conversion can be sufficiently low that undesirably large quantities of the prodrug must be taken to achieve desired effects. This itself can have undesirable side effects.
It is advantageous in many instances to have a prodrug that may be administered in a convenient form, such as by oral, or sublingual administration. Many prodrugs have not been amenable to such administration, however, because they tend to be broken down prior to absorption in vivo when administered in this fashion.
Accordingly, an object of the present invention is to provide compositions and methods that can be used to increase the in vivo concentration and bioavailability of the parent compound, 5-alkyl-7-hydroxy-isoflavone.
Another object of the invention according to certain aspects is to provide compounds and methods that can be used to increase the in vivo concentration and bioavailability of a parent 5-alkyl-7-hydroxy-isoflavone while being amenable to convenient administration, such as by oral, or sublingual administration.
Additional objects and advantages of the invention will be set forth in the description that follows, and in part will be apparent from the description, or may be learned by practice of the invention. The objects and advantages of the invention may be realized and obtained by means of the instrumentalities and combinations pointed out in the appended claims.
To achieve the foregoing objects, and in accordance with the purposes of the invention as embodied and broadly described in this document, a compound comprising an alkylcarbonate ester is provided. The compound represented by the formula I 
wherein R1 consists of a member selected from the group consisting of a straight-chain, branched, and cyclic alkyl; R2 consists of a member selected from the group consisting of a straight-chain, branched, and cyclic alkyl; R3 and R4 are the same or different, and selected from the group consisting of hydrogen, alkyl, hydroxy, and alkyoxy; and R5 consists of a member selected from the group consisting of hydrogen and an alkyl.
The alkylcarbonate ester optionally but preferably has an alkyl chain length of not more than 12, and more preferably of less than 11. The alkylcarbonate ester may consists of a member selected from the group consisting of methyl carbonate, ethyl carbonate, propyl carbonate, isopropyl carbonate, butyl carbonate, isobutyl carbonate, t-butyl carbonate, valeryl carbonate, hexyl carbonate, heptyl carbonate, octyl carbonate, nonyl carbonate, decyl carbonate, undecyl carbonate, dodecyl carbonate, cyclopentyl carbonate, cyclopentylmethyl carbonate, cyclopentylpropyl carbonate, cyclohexylmethyl carbonate, cyclohexylpropyl carbonate, and mixtures thereof. Alkyl carbonate esters having lower carbon chain lengths generally are preferred, although not universally so. The ethyl carbonate is a preferred form of the alkylcarbonate in the molecule. The compound itself according to this aspect of the invention may assume a number of specific forms. It may, for example, comprise 5-methyl-7-ethylcarbonate-isoflavone. It also may take the form of mixtures or combinations of compounds.
In accordance with a preferred variation of the first aspect of the invention, the compound has the following formula II 
wherein R1 consists of a member selected from the group consisting of a straight-chain, branched, and cyclic alkyl; and R2 consists of a member selected from the group consisting of a straight-chain, branched, and cyclic alkyl.
In accordance with a second aspect of the invention, a compound is provided for increasing the concentration of a parent isoflavone in a subject in vivo. The parent isoflavone has a skeletal structure including a 5 position and a 7 position and the parent isoflavone further has a 5 alkyl group, and a 7-hydroxy group comprising a 7-hydroxy oxygen appended to the 7 position and a 7-hydroxy hydrogen appended to the 7-hydroxy oxygen.
The compound of the second aspect of the invention comprises a substrate having the skeletal structure of the parent isoflavone. The substrate comprises a 5 position and a 7 position corresponding to the 5 and 7 positions respectively of the parent isoflavone. A straight-chain, branched, or cyclic alkyl group is appended to the 5 position. A promoiety is appended to the 7-hydroxy oxygen of the substrate as a substitute for the 7-hydroxy hydrogen of the parent isoflavone, the promoiety and the 7-hydroxy oxygen establishing an alkylcarbonate ester.
The substrate has the skeletal structure of the parent isoflavone, which is preferably 7-hydroxy-5-alkyl-isoflavone, and more preferably 7-hydroxy-5-methyl-isoflavone.
The alkylcarbonate ester may be as described above. For example, the alkylcarbonate ester optionally but preferably has a maximum alkyl chain length of 12 carbon atoms, and more preferably of less than 11 carbon atoms. The alkylcarbonate may, for example, be selected from the group consisting of methyl carbonate, ethyl carbonate, propyl carbonate, isopropyl carbonate, butyl carbonate, isobutyl carbonate, t-butyl carbonate, valeryl carbonate, hexyl carbonate, heptyl carbonate, octyl carbonate, nonyl carbonate, decyl carbonate, undecyl carbonate, dodecyl carbonate, cyclopentylmethyl carbonate, cyclopentyl carbonate, cyclopentylpropyl carbonate, cyclohexylmethyl carbonate, cyclohexylpropyl carbonate, and mixtures thereof. Alkyl carbonate esters having lower carbon chain lengths generally are preferred, although not universally so. Ethyl carbonate is a preferred form of the alkylcarbonate in the compound. The compound itself according to this aspect of the invention may assume a number of specific forms. It may, for example, comprise 5-methyl-7-ethylcarbonate-isoflavone. It also may take the form of mixtures or combinations of compounds.
In accordance with a third aspect of the invention, a method is provided for increasing the concentration of a parent isoflavone in a subject in vivo, the parent isoflavone having a skeletal structure including a 5 position and a 7 position and the parent isoflavone further having a 5 alkyl group, and a 7-hydroxy group comprising a 7-hydroxy oxygen appended to the 7 position and a 7-hydroxy hydrogen appended to the 7-hydroxy oxygen.
The method according to this third aspect of the invention comprises administering to the subject a compound comprising a substrate and a promoiety. The compound has the general formula I 
wherein R1 consists of a member selected from the group consisting of a straight-chain, branched, and cyclic alkyl; R2 consists of a member selected from the group consisting of a straight-chain, branched, and cyclic alkyl; R3 and R4 are the same or different, and selected from the group consisting of hydrogen, alkyl, hydroxy, and alkyoxy; and R5 consists of a member selected from the group consisting of hydrogen and an alkyl.
The method of this third aspect of the invention further comprises converting the compound in vivo into the parent isoflavone. The subject may be a human being, in which case the in vivo conversion comprises converting the compound into the parent isoflavone in vivo within the human being.
In accordance with a preferred variation of the third aspect of the invention, the compound has the following formula II 
wherein R1 consists of a member selected from the group consisting of a straight-chain, branched, and cyclic alkyl; and R2 consists of a member selected from the group consisting of a straight-chain, branched, and cyclic alkyl.
In accordance with a fourth aspect of the invention, a method is provided for increasing the concentration of a parent isoflavone in a subject in vivo, the parent isoflavone having a skeletal structure including a 5 position and a 7 position and the parent isoflavone further having a 5 alkyl group, and a 7-hydroxy group comprising a 7-hydroxy oxygen appended to the 7 position and a 7-hydroxy hydrogen appended to the 7-hydroxy oxygen.
According to this fourth aspect of the invention, a subject is administered a compound comprising a substrate and a promoiety. The substrate has the skeletal structure of the parent isoflavone comprising a 5 position, and a 7 position corresponding to the 5 and 7 positions respectively of the parent isoflavone. The 5 position has an alkyl substituent appended thereto. The promoiety is appended to the 7-hydroxy oxygen of the substrate as a substitute for the 7-hydroxy hydrogen of the parent isoflavone. The promojety and the 7-hydroxy oxygen establish an alkylcarbonate ester. The compound is converted in vivo into the parent isoflavone.
The alkylcarbonate ester of the third and fourth aspects of the invention may be as described above. In accordance with the third and fourth aspects of the invention, the compound administration may comprise peroral administration, transdermal administration, sublingual administration, and other means. Peroral administration is presently preferred.